Smith-Lemli-Opitz syndrome (SLOS)

O que é Smith-Lemli-Opitz syndrome (SLOS)?

Smith-Lemli-Opitz síndromes é uma doença genética variável caracterizada por crescimento lento antes e depois do nascimento. Acredita-se que ocorra em qualquer lugar a partir de 1 em 20-60,000 nascidos vivos.

Essa doença rara também é conhecida como distúrbio de anomalias congênitas múltiplas, apresentando-se com deficiência intelectual.

O síndromes é mais comum em caucasianos de ascendência centro-europeia. Mas extremamente raro entre as populações africanas e asiáticas.

Síndromes Sinônimos:
Acrodisgenital letal Síndromes Polidactilia, Inversão Sexual, Hipoplasia Renal e Rsh Pulmonar Unilobar Síndromes Anomalia Congênita Múltipla Letal Rutledge Síndromes Slo Síndromes

Quais mudanças genéticas causam Smith-Lemli-Opitz syndrome (SLOS)?

Mutações no gene DHCR7 levam à deficiência da enzima 7 desidrocolesterol redutase. Isso leva a níveis baixos de colesterol e à síndromes de Smith-Lemli-Opitz resultante. A síndrome é herdada em um padrão autossômico recessivo.

Herança autossômica recessiva significa que um indivíduo afetado recebe uma cópia de um gene mutado de cada um de seus pais, dando-lhes duas cópias de um gene mutado. Os pais que carregam apenas uma cópia da mutação do gene geralmente não apresentam sintomas, mas têm uma chance de 25% de transmitir as cópias das mutações do gene para cada um de seus filhos.

Quais são os principais sintomas de Smith-Lemli-Opitz syndrome (SLOS)?

Os sintomas podem variar de leves a moderados, mas os principais sintomas da síndromes de Smith-Lemli-Opitz são problemas comportamentais e de aprendizagem. A maioria dos indivíduos com a síndrome recebe um diagnóstico separado de autismo ou exibe tendências autistas. Comportamentos autolesivos e agressivos também estão frequentemente presentes em indivíduos com a síndrome.

As características faciais típicas da síndrome incluem uma ponte nasal larga, queixo pequeno, orelhas inseridas baixas, palato arqueado alto, lábio superior longo, mandíbula pequena, orelhas grandes e pálpebras caídas. Alguns indivíduos nascem com dedos das mãos e / ou pés extras, e a fusão do 2 e 3 dedo do pé é uma característica comum da síndrome.

Outros sintomas incluem problemas crônicos de sono, fotossensibilidade, outros problemas sensoriais, anormalidades genitais e vários defeitos congênitos (deficiências congênitas), incluindo aqueles relacionados ao coração, trato gastrointestinal, pulmões e rins.

Como alguém faz o teste de Smith-Lemli-Opitz syndrome (SLOS)?

O teste inicial para Smith-Lemli-Opitz síndromes pode começar com a triagem de análise facial, por meio do FDNA Telehealth plataforma telegenética, que pode identificar os principais marcadores do síndromes e delineia a necessidade de mais testes. Seguirá uma consulta com um conselheiro genético e, em seguida, um geneticista. 

Com base nesta consulta clínica com um geneticista, as diferentes opções de teste genético serão compartilhadas e o consentimento será solicitado para testes adicionais.   

Possíveis traços / características clínicas:
Herança autossômica recessiva, Fotossensibilidade cutânea, Má sucção, Polidactilia pós-axial da mão, Polidactilia pós-axial do pé, Orelhas giradas posteriormente, Heterotopia periventricular, Dedo sobreposto, Sindactilia do dedo do pé, Persistência do canal arterial, Agenesia renal, Cisto renal, Hipopoplasia da junção , Otite média recorrente, Pescoço curto, Vagina septada, Convulsão, Auto-mutilação, Puberdade precoce, Esclerocórnea, Nistagmo, Deficiência auditiva neurossensorial, Hipoplasia renal, Atrofia óptica, Cifose, Hipertelorismo, Hipertonia, Holoprosencefalia, Hidrocefalia, Hiperatividade, Hidropigrosis cabelo, Útero bicorno, Dedo do pé curto, Hipocolesterolemia, Hipoplasia dos lobos frontais, Hipoplasia do pênis, Hipoplasia do corpo caloso, Polegar curto, Hipospádia, Hipotonia generalizada, Glaucoma, Supercrescimento gengival, Ponte nasal deprimida, Disfunção gastroesofágica curta, estatura, deficiência auditiva, martelo, Microcefalia, escoliose

Informações médicas sobre Smith-Lemli-Opitz Síndromes

Smith-Lemli-Opitz syndrome is a disorder of cholesterol metabolism with a widely variable phenotype ranging from multiple congenital anomalies to normal development. The features may include microcephaly, growth retardation, cleft palate, cardiac defects, underdeveloped external genitalia in males, and 2-3 syndactyly of the toes. This autosomal-recessive disorder is caused by homozygous mutations in the DHCR7 gene on chromosome 11q13​.4. The facial features consist of microcephaly with bi-temporal narrowing, ptosis, anteverted nostrils, a broad nasal tip, prominent lateral palatine ridges, and micrognathia. Ocular abnormalities can include cataracts and optic atrophy (Atchaneeyasakul et al., 1998). In the hands, the index finger can overlap the middle finger, and the thumb can be short with a short 1st metacarpal. There is significant 2-3 syndactyly of the toes and, in males, hypospadias and a hypoplastic scrotum. Various internal malformations have been reported including pyloric stenosis, cleft palate, pancreatic anomalies, and lung segmentation defects.

The incidence of this condition has been estimated to be about 1 in 20,000 - 25,000 in a European Canadian population in Ontario (Nowaczyk et al., 2001 and Waye et al., 2002). Nowaczyk et al., (2001) found that the carrier rate for SLO in Caucasians might be as high as 1 in 30. Wright et al., (2003) reported a carrier frequency of 0.73% in African Americans.

De Die-Smulders and Fryns (1992) presented the clinical features in two adult brothers, which can be significantly different from the picture in childhood. It is instructive to look at the adult facial photographs in this paper. The diagnosis was subsequently confirmed biochemically.

There is evidence for two separate types of SLOS, one of which is lethal in the neonatal period. Cherstvoy et al., (1984) and Donnai et al., (1986) review the evidence for the severe lethal form, which is reviewed under Smith-Lemli-Opitz II.

Irons et al., (1993) and Tint et al., (1994) reported cases where plasma cholesterol concentrations were very low. 7-dehydrocholesterol was raised, however, and the authors postulated a defect in the enzyme that reduces the C-7,8 double bond of the latter intermediate.

Acosta (1994) discusses a high cholesterol diet as treatment for SLO syndrome. Jira et al., (1997) advocated a treatment regimen consisting of exchange transfusion in combination with inhibition of de novo cholesterol synthesis. Starck et al., (2002) combined a high cholesterol diet with a statin (simvastatin) in two patients. Levels of 7DHC were reduced, but one patient had a raised creatine kinase level, and the other had hepatotoxic side effects, so the drug had to be discontinued.

Tint et al., (1995) studied 24 individuals with Type I disease and found survival correlated strongly with higher plasma cholesterol levels.

Waterham et al., (1998) and Wassif et al., (1998) reported mutations in the 7-dehydrocholesterol (7-DHC) reductase gene.

Canick et al., (1997) suggest that maternal urinary estriol levels may be low, as well as maternal serum unconjugated estriol (uE3). However, they emphasize that the data on this are very sparse.

McGaughran et al., (1994, 1995), Tint et al., (1994), Abuelo et al., (1995), Mills et al., (1996), and Kratz and Kelley (1999) reported prenatal diagnosis by measuring 7-dehydrocholesterol (7-DHC) levels in amniotic fluid. Tint et al., (1998) showed that prenatal diagnosis can be carried out accurately by measuring amniotic fluid dehydrocholesterols.

It should be noted that Porter et al., (1996) report that cholesterol is covalently attached to the amino-terminal signaling domain of the hedgehog protein, which may explain some of the developmental anomalies in Smith-Lemli-Opitz syndrome.

Kolf-Clauw et al., (1996) reported a rat model by inhibiting 7-dehydrocholesterol reductase with the teratogen AY9944. The rats have features of holoprosencephaly.

Kelley et al., (1996) reported four patients with evidence of semilobar holoprosencephaly who were shown to have the biochemical features of Smith-Lemli-Opitz syndrome.

Sharp et al., (1997) carried out prenatal diagnosis by measuring 7-DHC in a chorionic villus biopsy.

Irons and Tint (1998) review the experience with prenatal diagnosis.

Anderson et al., (1998) reported a brother and sister with features of the condition but with a milder manifestation. They were found to have mildly depressed plasma cholesterol levels and increased 7-dehydrocholesterol levels, although less marked than in classical Smith-Lemli-Opitz syndrome. The parents also had significantly elevated levels of 7-dehydrocholesterol in lymphoblasts.

Nowaczyk et al., (1998) also reported three cases with milder clinical features. These were two brothers and their female first cousin. The family was not consanguineous. There appeared to be no facial features of the condition in the female cousin, and her 7-dehydrocholesterol levels were 20-25% of her affected cousins. The possibility that she might be a heterozygote was not discussed. De Die-Smulders et al., (1996) and Ryan et al., (1998) stress the variability of the condition.

Worthington and Goldblatt (1997) reported a case with oligodactyly and a cleft hand appearance. De Jong et al., (1998) reported a similar case with the severe type 2 phenotype. However, see Bodamer and Craigen (1999) for a query about the biochemical diagnosis of this case.

Charman et al., (1998) reported a 5-year-old girl with the condition who had photosensitivity.

Krajewska-Walaseek et al., (1999) also studied the phenotype at different ages. They note that an open-mouth appearance with pouting lips becomes a feature in older children.

Kelley and Hennekam (2000) provide a detailed clinical overview of the condition. Kelley and Hennekam (2000) and Nowaczyk and Waye (2001) provide good reviews of the clinical, biochemical, and genetic features.

Tierney et al., (2001) studied the behavioral phenotype in 56 cases. Eighty-nine percent had a history of repeated self-injury, 54% bit themselves, 48% had head-banging, and 54% threw themselves backwards in a characteristic upper body movement. Of the 11 subjects over 10 years of age, 27% had stereotypic stretching motions of the upper body accompanied by hand flapping. There was also hyperactivity and sleep disturbance. Fifty-three percent of the cases met the diagnostic criteria for autistic disorder.

Witsch-Baumgartner et al., (2000) reported mutations in 84 patients and provided some evidence for genotype-phenotype correlation. However, in a study of 32 patients by Yu et al., (2000) no phenotype-genotype correlation could be demonstrated.

Further cases with a mild phenotype were reported by Prasad et al., (2002); Mueller et al., (2003) (with Hirschsprung disease); and Langius et al., (2003).

It is interesting to note that the maternal apo E genotype might be a modifier of the syndrome (Witsch-Baumgartner et al., 2004).

Battaile et al., (1999) developed a PCR assay for the IVS8-1G->C mutation, which is relatively common. De Brasi et al., (1999) reported further mutations in the Italian population and evidence suggesting the T93M mutation is common in that population.

Yu et al., (2000) showed that the IVS8-1G->C splice acceptor site mutation is found in 60% of cases in the U.S. population. Waterham et al., (2000) found this mutation in 35% of affected alleles and, combining their results with the literature, suggested that 25% of affected alleles have this mutation. The IVS8-1G->C mutation was also found in individuals of Afro-Caribbean origin.

Nowaczyk et al., (2001) reported a fetus with holoprosencephaly who was shown to have the condition. There was a IVS8-1G->C homozygous mutation. Two other patients were reported where the same homozygous mutation was found. Although they had a severe phenotype, they did not have holoprosencephaly.

Nguyen et al., (2003) reported a 20-year-old male with developmental delay and physical features of Smith-Lemli-Opitz who had profound hypocholesterolemia but with normal 7DHC levels. The hypocholesterolemia was thought to be due to familial hypobetalipoproteinemia, which was present in other normal family members.

Sikora et al., (2006) also stressed the high frequency of autism or related behavioral problems in SLOS.

Note that some patients with mutations can have a very mild phenotype (Jezela-Stanek et al., 2008).

Quelin et al., (2012) identified 10 molecularly proven fetal cases and examined the pathology. Additional features found were ulnar hypoplasia, vertebral segmentation defects, gastroschisis, lung fusion, pulmonary adenomatoid malformation, and hypothalamic hamartomas. The fetal faces were typical of the syndrome.

Movassaghi et al., (2017) compared levels of 25-hydroxyvitamin D between 53 Smith-Lemli-Opitz patients and a control group. The authors found increased levels of 5-hydroxyvitamin D, as well as higher blood calcium levels, in Smith-Lemli-Opitz patients. None of the patients had vitamin D toxicity.

Prosnitz et al., (2017) described five male patients with Smith-Lemli-Opitz syndrome and pulmonary vein stenosis. Three patients died from this condition.

* This information is courtesy of the L M D.
If you find a mistake or would like to contribute additional information, please email us at: [email protected]

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